Alzheimer’s disease (AD) is one of the leading causes of death throughout the world, yet there is no treatment available to cure this disease. It is primarily characterized by progressive memory decline and cognitive deficits, which eventually interrupt one’s daily living and functioning. A key neuropathological hallmark of AD is the deposition of Aβ, with its oligomeric form being the most toxic species. Aβ oligomers are known to cause synaptic dysfunction and neuronal damage, making them a central target of AD research. However, despite countless efforts, there is still no effective therapeutic options, and this may be in part due to the multifaceted nature of AD. Therefore, this thesis aims to explore the actions of Aβ oligomers to better understand their potential roles in AD pathogenesis. The first aim was to examine the effects of Aβ on human brain microvascular endothelial cells (HBMVECs) to identify the impact on the bloodbrain barrier (BBB). This study shows that Aβ endocytosis into HBMVECs is associated with RAGE and disrupts the BBB integrity, as well as key intracellular processes such as molecular transport and degradation system through the endosomal trafficking pathway. Furthermore, Aβ oligomers also dysregulate lipid metabolism which results in increased cholesterol level. The second aim of this thesis was to study the effects of oligomeric Aβ in protein turnover. Aβ oligomers increased
de novo protein synthesis in rat primary cortical neurons which coincided with synaptic degeneration. The upregulation of newly synthesized proteins was restored by eFT508, an MNK1/2 inhibitor, suggesting that this abnormal protein synthesis machinery may be dependent on the MNK signaling pathway. The final aim of this thesis was to detect multi-synapses in vivo and in vitro. EM imaging analysis results revealed the presence of complex multi-spine boutons (MSBs) in human AD brains, whereas such complexity was absent in control brains. The number of MSBs did not change between groups. This may suggest aberrant synaptic connectivity in AD. Furthermore, expansion microscopy allowed to visualize these multi-synaptic structures using conventional confocal microscopy, offering a valuable tool for future investigation of multi-synapses. In summary, this thesis explores the role of Aβ oligomers involved in multiple pathways that contribute to AD progression. By exploring the specific roles of oligomeric Aβ in specific cell types, this work sheds light on the complex and multifaceted nature of AD and provides insights into potential therapeutic strategies.
Investigation of amyloid actions in Alzheimer's disease
Lee, S. (Author). 1 Apr 2025
Student thesis: Doctoral Thesis › Doctor of Philosophy